Pharmacokinetic Interaction between 4′-Epidoxorubicin and the Multidrug Resistance Reverting Agent Quinine

Abstract

The serum and red blood cell (RBCs) disposition of epirubicin (EPR) after intravenous bolus injection without and with coadministered quinine (QUI) was investigated in patients undergoing a cyclic chemotherapy with EPR. QUI possesses a statistical significant influence on the EPR serum concentrations and, as a consequence, on the pharmacokinetic parameters for the initial distribution phase of EPR. Within the first 15 min after administration, EPR was distributed from the central compartiment distinctly faster in compare to the control, when QUI was preadministered (t1/2 = 6 min for the control group and t1/2 = 3 min with QUI; -46% , p < 0.05). Yet, in the beta-phase when drug-elimination predominates, no statistical significant influence of QUI in regard to EPR serum and RBC concentrations could be observed. Half-life of elimination was 9.5 h for the control group and 8.6 h for the QUI group (-10% ). The mean initial serum concentration (c0) was reduced significantly by QUI from 7359 ± 506 ng/ml to 4351 ± 1682 ng/ml (-42 % . p < 0.005). Furthermore. QUI caused a reduction of the serum bioavailability of EPR (expressed as AUC0-24-values) from 3404 ± 1008 ng/ml × h to 2359 ± 1073 ng/ml × h (-3 1 % , p < 0.05). Vd and Vdß were increased at about 90% and the mean total body clearance was accelerated from 45.3 to 148.7 ml/min, but due to the large standard deviations the calculated difference for these parameters was not statistically significant. In the observed time interval of 24 h, the red blood cell coefficient of distribution kRBC of EPR was lower if QUI was coadministered (kRBC = 1.25 ± 0.12 for the control group kRBC = 1.15 ± 0.13 under QUI; p < 0.04). The results point out that QUI induces an accelerated distribution of EPR from the blood into the tissue and that QUI additionally may have influence on the red-blood cell partitioning of EPR.

Inhibition of glutathione S‐transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance

“…62,63 The results obtained in our study, showing that quinine is an effective inhibitor of GST P1-1 in vitro, suggest that inhibition of GST P1-1 in vivo may be one of the mechanisms to explain the effects of quinine as a chemomodulator in clinical studies. Studies have demonstrated that there is a tendency for simultaneous expression of P-170 and GST P1-1 in some cancer types.…”